The present invention provides novel compounds, compositions, methods of their use and methods of their manufacture, such compounds believed to be pharmacologically useful to induce analgesia in mammals. More specifically, the compounds of the present invention are orally active dimethyl tyrosyl amide sulfides, sulfones and sulfoxides which, by acting as neurotransmitters or neuromodulators in the central nervous system central pain-suppressant system, induce analgesia.
Opioids are a group of drugs that are, to varying degrees, opium-like or morphine-like in their properties. The opioids are employed primarily as analgesics, but they have many other pharmacological effects as well, and they share some of the properties of certain naturally occurring peptides. By 1967, researchers had concluded that the complex interactions among morphine-like drugs, morphine antagonists, and mixed morphine agonist-antagonists could best be explained by postulating the existence of more than one type of receptor for the opioids and related drugs. Subsequent research revealed that there are three distinct families of opioid peptides, the endorphins, the enkephlins and the dynorphans, and multiple categories of opioid receptors. Although studies of the binding of opioid drugs and peptides to specific sites in brain and other organs has suggested the existence of perhaps as many as eight different types of opioid receptors, in the CNS there is reasonably firm evidence for three major categories of receptors, designated .mu., .kappa., and .delta..
The classical antagonist, naloxone, has been found to bind with high affinity to all opioid receptors although its affinity for .mu. receptors is generally more than ten times higher than for 6 receptor sites. In 1975, Hughes and Kosterlitz described the isolation of two pentapeptides that exhibited morphine-like actions--actions that were specifically antagonized by naloxone. The same year, Goldstein and colleagues reported the presence of peptide-like substances in the pituitary gland with opioid activity. The peptide appears to act as a neurotransmitter or neuromodutator in the CNS. The natural peptide binds stereos specifically to partially purified brain opiate receptor sites, see for example, Bradberry et al., Nature, 260,793 (1976). The natural peptide is also highly active in bioassays for opiate activity but exhibits only weak, fleeting analgesic activity when injected directly into the brain of the rat, see for example, Belluzi et al., Nature, 260,625 (1976). In order to overcome the lack of in vivo activity, a number of investigators have made numerous modifications to methionine enkephalin, which was the original pentapeptide reported by Hughes et al. Among such modifications have been the synthesis and activity of short chain enkephalin-like peptides, among them tripeptide and dipeptide alkylamides by Kiso et al., "Peptide Chemistry 198l," 65-70, Protein Research Foundation, Osaka, Japan (1982). Vavrek, et al., Peptides 2,303, 1981, disclosed analogs of enkephalin, among them the dipeptide tyrosine-D-alanine-phenylpropylamide.
The compounds of this invention are non-peptide opioid agonists that act primarily at the .mu. receptor, having preferential affinity for the .mu. receptor over the 6 receptor of 30-100 fold. The compounds of this invention have unexpected and surprisingly superior properties when compared to the di, tri, tetra and pentapeptides of the prior art. The present invention provides new tyrosyl amide sulfide, sulfoxide and sulfone derivatives which show improved potency as analgesic agents by both oral and parenteral routes of administration.